Hepatitis b antiviral agents

ABSTRACT

The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts, esters, or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     which inhibit the protein(s) encoded by hepatitis B virus (HBV) or interfere with the function of the HBV life cycle of the hepatitis B virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HBV infection. The invention also relates to methods of treating an HBV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/649,993, filed on Mar. 29, 2018. The entire teachings of the aboveapplication are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates generally to novel antiviral agents.Specifically, the present invention relates to compounds which caninhibit the protein(s) encoded by hepatitis B virus (HBV) or interferewith the function of the HBV life cycle, compositions comprising suchcompounds, methods for inhibiting HBV viral replication, methods fortreating or preventing HBV infection, and processes for making thecompounds.

BACKGROUND OF THE INVENTION

HBV infection remains a major public health problem, affectingapproximately 2 billion people worldwide. Among them, 350 million peopleworldwide and 1.4 million in the US develop a chronic infection, whichcan lead to chronic persistent hepatitis, liver cirrhosis, andhepatocellular carcinoma (HCC). Every year 500,000 to 1 million peopledie from the end stage of liver diseases caused by HBV infection.

Despite the availability of a prophylactic HBV vaccine, the burden ofchronic HBV infection continues to be a significant unmet worldwidemedical problem, due to suboptimal treatment options and sustained ratesof new infections in most parts of the developing world. Currenttreatments do not provide a cure and are limited to only two classes ofagents (interferon and nucleoside analogues/inhibitors of the viralpolymerase); drug resistance, low efficacy, and tolerability issueslimit their impact. The low cure rates of HBV are attributed at least inpart to the presence and persistence of covalently closed circular DNA(cccDNA) in the nucleus of infected hepatocytes. However, persistentsuppression of HBV DNA slows liver disease progression and helps toprevent HCC. Current therapy goals for HBV-infected patients aredirected to reducing serum HBV DNA to low or undetectable levels, and toultimately reducing or preventing the development of cirrhosis and HCC.

The HBV is an enveloped, partially double-stranded DNA (dsDNA) virus ofthe hepadnavirus family (Hepadnaviridae). HBV capsid or core protein(CP) plays essential roles in HBV replication. The predominantbiological function of capsid protein is to act as a structural proteinto encapsidate pre-genomic RNA and form immature capsid particles, whichspontaneously self-assemble from many copies of core dimers in thecytoplasm. Capsid protein also regulates viral DNA synthesis throughdifferent phosphorylation status of its C-terminal phosphorylationsites. Also, capsid protein might facilitate the nuclear translocationof viral relaxed circular genome by means of the nuclear localizationsignals located in the Arginine-rich domain of the C-terminal region ofcapsid protein. In the nucleus, as a component of viral cccDNAminichromosome, capsid protein could play a structural and regulatoryrole in the functionality of cccDNA minichromosomes. Capsid protein alsointeracts with viral large envelope protein in endoplasmic reticulum(ER) and triggers the release of intact viral particles fromhepatocytes.

Capsid related anti-HBV inhibitors have been reported. For example,phenylpropen-amide derivatives, including compounds named AT-61 andAT-130 (Feld J. et al. Antiviral Res. 2007, 76, 168), and a class ofthiazolidin-4-ones from Valeant (WO 2006/033995), have been shown toinhibit pregenomic RNA (pgRNA) packaging. Heteroaryldihydro-pyrimidinesor HAPs were discovered in a tissue culture-based screening (Weber etal., Antiviral Res. 2002, 54, 69). These HAP analogs act as syntheticallosteric activators and are able to induce aberrant capsid formationthat leads to degradation of the core protein. A subclass ofsulphamoylarylamides shows activity against HBV (WO2013/006394,WO2013/096744, WO2014/184365, and WO 2017/136403). It was also shownthat the small molecule bis-ANS acts as a molecular ‘wedge’ andinterferes with normal capsid-protein geometry and capsid formation(Zlotnick A. et al. J. Virol. 2002, 4848).

There is a need in the art for novel therapeutic agents that treat,ameliorate or prevent HBV infection. Administration of these therapeuticagents to an HBV infected patient, either as monotherapy or incombination with other HBV treatments or ancillary treatments, will leadto significantly improved prognosis, diminished progression of thedisease, and enhanced seroconversion rates.

SUMMARY OF THE INVENTION

The present invention relates to novel antiviral compounds,pharmaceutical compositions comprising such compounds, as well asmethods to treat or prevent viral (particularly HBV) infection in asubject in need of such therapy with said compounds. Compounds of thepresent invention inhibit the protein(s) encoded by hepatitis B virus(HBV) or interfere with the life cycle of HBV and are useful asantiviral agents. In addition, the present invention includes methodsfor preparing the compounds of the invention.

In its principal aspect, the present invention provides a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

W and Y are each N and Z is CR¹⁰; or W is C, one of Y and Z is N and theother is NR¹¹; R¹⁰ is hydrogen, halo, or optionally substituted C₁-C₆alkyl; R¹¹ is hydrogen, optionally substituted C₁-C₆ alkyl, oroptionally substituted C₃-C₈ cycloalkyl; or W, Y and Z are each N;preferably W and Y are N, and Z is CH; or W is C, one of Y and Z is N,and the other is NH or optionally substituted NMe; or W, Y and Z areeach N.

R¹ and R³ are independently hydrogen or optionally substituted C₁-C₆alkyl; preferably R¹ and R³ are hydrogen or optionally substitutedmethyl;

R² is selected from a group consisting of optionally substituted C₃-C₆cycloalkyl, optionally substituted C₃-C₈ cycloalkenyl, optionallysubstituted 3- to 8-membered heterocyclic, optionally substituted aryl,and optionally substituted heteroaryl;

R⁴ is selected from the group consisting of hydrogen, halo, hydroxy,protected hydroxy, amino, optionally substituted amino, optionallysubstituted C₁-C₆ alkyl, and optionally substituted C₁-C₆ alkoxy;

Alternatively, R¹ and R³ are taken together with the carbon atoms towhich they are attached to form an olefinic double bond;

Alternatively, R¹ and R² are taken together with the carbon atom towhich they are attached to form a group consisting of optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₃-C₈ cycloalkenyl,or optionally substituted 3- to 8-membered heterocyclic;

Alternatively, R² and R⁴ are taken together with the carbon atoms towhich they are attached to form optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₃-C₈ cycloalkenyl, or optionally substituted 3-to 8-membered heterocyclic;

Alternatively, R¹, R², R³ and R⁴ are taken together with the carbonatoms to which they are attached to form optionally substituted aryl oroptionally substituted heteroaryl;

Alternatively, R³ and R⁴ are taken together with the carbon atom towhich they are attached to form optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₃-C₈ cycloalkenyl, or optionally substituted 3-to 8-membered heterocyclic;

R⁵ is selected from the group consisting of optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₈ alkenyl, optionally substitutedC₂-C₈ alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted 3- to 8-membered heterocyclic, optionally substituted aryl,optionally substituted heteroaryl, and -L-R¹²; wherein L is selectedfrom the group consisting of —O—, —S—, —NR¹¹—, —C(O)—, —C(O)O—, —OC(O)—,—C(O)N(R¹¹)—, —N(R¹¹)C(O)—, —OC(O)N(R¹¹)—, —N(R¹¹)C(O)O—,—N(R¹¹)C(O)N(R¹¹)—, —S(O)—, —S(O)₂—, —S(O)₂N(R¹¹)—, —N(R¹¹)S(O)₂—,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted 3- to 8-membered heterocyclic,optionally substituted aryl, and optionally substituted heteroaryl; andR¹² is selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted 3- to 8-membered heterocyclic, optionallysubstituted aryl, and optionally substituted heteroaryl;

-   -   R⁶ is hydrogen or optionally substituted C₁-C₆ alkyl; and    -   R⁷ is optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted C₁-C₆ alkyl, or optionally        substituted C₃-C₈ cycloalkyl.

Each preferred group stated above can be taken in combination with one,any or all other preferred groups.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present invention is a compound of Formula (I)described above, or a pharmaceutically acceptable salt thereof.

In one embodiment, W and Y are each N and Z is CR¹⁰. In certainembodiments, W and Y are each N and Z is CH.

In certain embodiments, W is C, one of Y and Z is N and the other isNR¹¹. In certain embodiments, W is C, one of Y and Z is N and the otheris NR¹¹, where R₁₁ is hydrogen or optionally substituted methyl.

In certain embodiments, W, Y and Z are each N.

In certain embodiments, the present invention relates to compounds ofFormula (I) and pharmaceutically acceptable slats thereof, wherein R¹,R³ and R⁶ are independently hydrogen or optionally substituted C₁-C₆alkyl. In certain embodiments, R¹, R³ and R⁶ are independently hydrogenor optionally substituted methyl.

In certain embodiments the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R⁵is -L-R¹²; wherein L is selected from the group consisting of —O—, —S—,—NR¹¹—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R¹¹)—, —N(R¹¹)C(O)—,—OC(O)N(R¹¹)—, —N(R¹¹)C(O)O—, —N(R¹¹)C(O)N(R¹¹)—, —S(O)—, —S(O)₂—,—S(O)₂N(R¹¹)—, and —N(R¹¹)S(O)₂—; R¹¹ and R¹² are previously defined.

In certain embodiments the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R⁵is optionally substituted phenyl or optionally substituted heteroaryl.In certain embodiments, R⁵ is phenyl or heteroaryl substituted with oneor more substituents, such as 1, 2, 3, 4 or 5 substituents. Preferablythe substituents are independently selected from halogen, CN, optionallysubstituted —C₁-C₃ alkoxy, optionally substituted —C₁-C₃ alkyl, andoptionally substituted —C₃-C₆ cycloalkyl. In certain embodiments, R⁵ isphenyl or heteroaryl substituted with one or more substituentsindependently selected from fluoro, chloro, bromo, methyl,difluoromethyl, trifluoromethyl, CN and cyclopropyl.

In certain embodiments the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R⁵is an aryl or heteroaryl group derived from one of the following byremoval of one hydrogen atom:

wherein each of the above shown groups is optionally substituted, and isconnected to the pyrazole or triazole ring through a carbon atom or,where possible, a nitrogen atom. In certain embodiments, each of thesegroups independently selected from halogen and C₁-C₄-alkyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R⁵is optionally substituted 3- to 8-membered heterocyclic.

In certain embodiments the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R⁵is a heterocyclic group derived from one of the following by removal ofone hydrogen atom:

wherein each of the above shown groups is optionally substituted, and isconnected to the pyrazole or triazole ring through a carbon or nitrogenatom. In certain embodiments, each of these groups is connected to thepyrazole or triazole ring through a nitrogen atom. In certainembodiments, each of these groups is substituted with one or moresubstituents independently selected from C₁-C₆-alkyl, aryl, heteroaryl,C₃-C₆-cycloalkyl, spiro-C₃-C₆-cycloalkyl and fused C₃-C₆-cycloalkyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and their pharmaceutically acceptable salts thereof,wherein R⁷ is optionally substituted phenyl. In certain embodiments, R⁷is phenyl substituted with one or more substituents, such as 1, 2, 3, 4or 5 substituents. Preferably the substituents are independentlyselected from halogen, CN, optionally substituted —C₁-C₃ alkoxy,optionally substituted —C₁-C₃ alkyl, and optionally substituted —C₃-C₆cycloalkyl. In certain embodiments, R⁷ is phenyl substituted with one ormore substituents independently selected from fluoro, chloro, bromo,methyl, difluoromethyl, trifluoromethyl, CN, methoxy, hydroxyl,isopropyl and cyclopropyl. In certain embodiments, R⁷ is selected fromthe groups below:

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R⁷is optionally substituted monocyclic heteroaryl. In certain embodiments,the present invention relates to compounds of Formula (I) or, andpharmaceutically acceptable salts thereof, wherein R⁷ is optionallysubstituted thiophenyl, optionally substituted thiazolyl, optionallysubstituted pyridyl, or optionally substituted pyrimidinyl. In certainembodiments, the present invention relates to compounds of Formula (I)and pharmaceutically acceptable salts thereof, wherein R⁷ is optionallysubstituted pyrimidinyl, optionally substituted pyridazyl, or optionallysubstituted pyrazyl as shown below:

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R⁷is optionally substituted bicyclic heteroaryl. In certain embodiments,the present invention relates to compounds of Formula (I), andpharmaceutically acceptable salts thereof, wherein R⁷ is optionallysubstituted 5/6 or 6/6 bicyclic heteroaryl. In certain embodiments, R⁷is optionally substituted 5/6 bicyclic heteroaryl and is connected tothe nitrogen atom of —NH(CO)— through a carbon atom of the 6-memberedring of said 5/6 bicyclic heteroaryl. In certain embodiments, thepresent invention relates to compounds of Formula (I), andpharmaceutically acceptable salts thereof, wherein R⁷ is optionallysubstituted benzimidazolyl, benzothiazolyl, benzoxazolyl, indazolyl,quinolyl, isoquinolyl or quinazolyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R⁷is optionally substituted C₁-C₆ alkyl or optionally substituted C₃-C₈cycloalkyl.

In certain embodiments, the present invention relates to compounds ofFormula (I) and pharmaceutically acceptable salts thereof, wherein R¹and R² are taken together with the carbon atom to which they areattached to form an optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted C₃-C₈ cycloalkenyl, or optionally substituted 3- to8-membered heterocyclic. In certain embodiments, R¹, R² and the carbonatom to which they are attached form a C₃-C₅ cycloalkyl.

In certain embodiments, the present invention relates to compounds ofFormula (Ia), and pharmaceutically acceptable salts thereof,

wherein L, W, Y, Z, R¹, R², R³, R⁴, R⁶, R⁷, and R¹² are as previouslydefined.

In certain embodiments the present invention relates to compounds ofFormula (Ia), and pharmaceutically acceptable salts thereof, wherein Lis —O—, —N(R¹¹)C(O)—, —OC(O)N(R¹¹)—, —N(R¹¹)C(O)O—, —N(R¹¹)C(O)N(R¹¹)—,or —N(R¹¹)S(O)₂—.

In certain embodiments the present invention relates to compounds ofFormula (Ia), and pharmaceutically acceptable salts thereof, wherein Lis optionally substituted phenyl or optionally substituted heteroaryl.In certain embodiments the present invention relates to compounds ofFormula (Ia), and pharmaceutically acceptable salts thereof, wherein Lis optionally substituted C₃-C₈ cycloalkyl or optionally substituted 3-to 8-membered heterocyclic.

In certain embodiments the present invention relates to compounds ofFormula (Ia), and pharmaceutically acceptable salts thereof, wherein Lis an aryl or heteroaryl group derived from one of the following byremoval of two hydrogen atoms:

wherein each of the above shown groups is optionally substituted and isconnected to the remainder of the molecule through carbon or, wherepossible, nitrogen atoms.

In certain embodiments the present invention relates to compounds ofFormula (Ia), and pharmaceutically acceptable salts thereof, wherein Lis a heterocyclic group derived from one of the following by removal oftwo hydrogen atoms:

wherein each of the above shown groups is optionally substituted and isconnected to the remainder of the molecule through carbon or nitrogenatoms.

In certain embodiments the present invention relates to compounds ofFormula (Ia), and pharmaceutically acceptable salts thereof, wherein R¹²is an aryl or heteroaryl group derived from one of the following byremoval of one hydrogen atom:

wherein each of the above shown groups is optionally substituted and isconnected to L through a carbon atom or, where possible, a nitrogenatom.

In certain embodiments the present invention relates to compounds ofFormula (Ia), and pharmaceutically acceptable salts thereof, wherein R¹²is a heterocyclic group derived from one of the following by removal ofone hydrogen atom:

wherein each of the above shown groups is optionally substituted and isconnected to L through a carbon atom or a nitrogen atom.

In certain embodiments, the present invention relates to compounds ofFormula (II), and pharmaceutically acceptable salts thereof,

wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as previously defined.

In certain embodiments, the present invention relates to compounds ofFormula (II), and pharmaceutically acceptable salts thereof, wherein R²is selected from a group consisting of optionally substituted C₃-C₈cycloalkyl, optionally substituted C₃-C₈ cycloalkenyl, optionallysubstituted 3- to 8-membered heterocyclic, optionally substituted aryl,and optionally substituted heteroaryl.

In certain embodiments, the present invention relates to compounds ofFormula (II), and pharmaceutically acceptable salts thereof, wherein R²and R⁴ are taken together with the carbon atoms to which they areattached to form optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted C₃-C₈ cycloalkenyl, or optionally substituted 3- to8-membered heterocyclic. In certain embodiments, the present inventionrelates to compounds of Formula (II), and pharmaceutically acceptablesalts thereof, wherein R¹, R², R³ and R⁴ are taken together with thecarbon atoms to which they are attached to form optionally substitutedaryl or optionally substituted heteroaryl.

In certain embodiments, the present invention relates to compounds ofFormula (IIa), and pharmaceutically acceptable salts thereof,

wherein at least one of E¹, E², E³, E⁴, E⁵, and E⁶ is present, and E¹,E², E³, E⁴, E⁵, and E⁶ are each independently selected from the groupconsisting of absent, —CR¹³R¹⁴—, —NR¹¹—, —O—, —C(O)—, —S(O)—, —S(O)₂—,and —S—; R¹³ and R¹⁴ at each occurrence are independently selected fromthe group consisting of hydrogen, halo, and optionally substituted C₁-C₆alkyl; R¹, R³, R⁵, R⁶, R⁷, and R¹¹ are as previously defined.

In certain embodiments, E¹-E⁶ together form —(CH₂)_(n)—, where n is 1 to6. Preferably n is 1 to 4, and more preferably n is 3. In certainembodiments, E¹-E⁶ together form —(CH₂)_(o)—U—(CH₂)_(p)—, where o and pare each independently 0 to 3, provided that the sum of o and p is 2 to5, and U is —NR¹¹—, —O—, —C(O)—, —S(O)—, —S(O)₂—, or —S—.

In certain embodiments, compounds of Formula (IIa) have thestereochemistry shown in Formula (IIa-1) or Formula (IIa-2):

In preferred embodiments, compounds of Formula (IIa) have thestereochemistry shown in Formula (IIa-1).

In certain embodiments, compounds of Formula (IIa) can have thestereochemistry shown in Formula (IIa-3) or Formula (IIa-4),

In certain embodiments, the present invention relates to compounds ofFormula (III) or Formula (IV), and pharmaceutically acceptable saltsthereof,

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R¹¹ are as previously defined.

In certain embodiments, the present invention relates to compounds ofFormula (III), or Formula (IV), and pharmaceutically acceptable saltsthereof, wherein R² is selected from a group consisting of optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₃-C₈ cycloalkenyl,optionally substituted 3- to 8-membered heterocyclic, optionallysubstituted aryl, and optionally substituted heteroaryl.

In certain embodiments, the present invention relates to compounds ofFormula (III), or Formula (IV), and pharmaceutically acceptable saltsthereof, wherein R² and R⁴ are taken together with the carbon atoms towhich they are attached to form optionally substituted C₃-C₈ cycloalkyl,optionally substituted C₃-C₈ cycloalkenyl, or optionally substituted 3-to 8-membered heterocyclic. In certain embodiments, the presentinvention relates to compounds of Formula (III) or Formula (IV), andpharmaceutically acceptable salts thereof, wherein R¹, R², R³ and R⁴ aretaken together with the carbon atoms to which they are attached to formoptionally substituted aryl or optionally substituted heteroaryl.

In certain embodiments, the present invention relates to compounds ofFormula (IIIa) or Formula (IVa), and pharmaceutically acceptable saltsthereof,

wherein E¹, E², E³, E⁴, E⁵, E⁶, R¹, R³, R⁵, R⁶, R⁷, and R¹¹ are aspreviously defined.

In certain embodiments, compounds of Formula (IIIa) and Formula (IVa)can have the stereochemistry shown in Formula (IIIa-1) or Formula(IIIa-2) and Formula (IVa-1) or Formula (IVa-2) respectively.

In preferred embodiments, compounds of Formula (IIIa) and Formula (IVa)have the stereochemistry shown in Formula (IIIa-1) and Formula (IVa-1)respectively.

In certain embodiments, compounds of Formula (IIIa) and Formula (IVa)can have the stereochemistry shown in Formula (IIIa-3) or Formula(IIIa-4) and Formula (IVa-3) or Formula (IVa-4).

In certain embodiments, the present invention relates to compounds ofFormula (V), and pharmaceutically acceptable salts thereof,

wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as previously defined.

In certain embodiments, the present invention relates to compounds ofFormula (V), and pharmaceutically acceptable salts thereof, wherein R²is selected from a group consisting of optionally substituted C₃-C₈cycloalkyl, optionally substituted C₃-C₈ cycloalkenyl, optionallysubstituted 3- to 8-membered heterocyclic, optionally substituted aryl,and optionally substituted heteroaryl.

In certain embodiments, the present invention relates to compounds ofFormula (V), and pharmaceutically acceptable salts thereof, wherein R²and R⁴ are taken together with the carbon atoms to which they areattached to form optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted C₃-C₈ cycloalkenyl, or optionally substituted 3- to8-membered heterocyclic. In certain embodiments, the present inventionrelates to compounds of Formula (V), and pharmaceutically acceptablesalts thereof, wherein R¹, R², R³ and R⁴ are taken together with thecarbon atoms to which they are attached to form optionally substitutedaryl or optionally substituted heteroaryl.

In certain embodiments, the present invention relates to compounds ofFormula (Va), and pharmaceutically acceptable salts thereof,

wherein at least one of E¹, E², E³, E⁴, E⁵, and E⁶ is present, and E¹,E², E³, E⁴, E⁵, and E⁶ are each independently selected from the groupconsisting of absent, —CR¹³R¹⁴—, —NR¹¹—, —O—, —C(O)—, —S(O)—, —S(O)₂—,and —S—; R¹³ and R¹⁴ at each occurrence are independently selected fromthe group hydrogen, halo, or optionally substituted C₁-C₆ alkyl; R¹, R³,R⁵, R⁶, R⁷, and R¹¹ are as previously defined.

In certain embodiments, compounds of Formula (Va) have thestereochemistry shown in Formula (Va-1) or Formula (Va-2):

In preferred embodiments, compounds of Formula (Va) have thestereochemistry shown in Formula (Va-1).

In certain embodiments, compounds of Formula (Va) can have thestereochemistry shown in Formula (Va-3) or Formula (Va-4),

In certain embodiments, the present invention relates to compounds ofFormula (VI), and pharmaceutically acceptable salts thereof,

wherein W, Y, Z, E¹, E², E³, E⁴, E⁵, E⁶, R¹, R³, R⁵, R⁶, and R⁷ are aspreviously defined.

In certain embodiments, the present invention relates to compounds ofFormula (VIIa), Formula (VIIb), Formula (VIIc), or Formula (VIId), andpharmaceutically acceptable salts thereof,

wherein W, Y, Z, R¹, R³, R⁴, R⁵, and R⁷ are as previously defined.

In certain embodiments, the present invention relates to compounds ofFormula (VIIa), Formula (VIIb), Formula (VIIc), or Formula (VIId), andpharmaceutically acceptable salts thereof, wherein R⁷ is selected fromthe groups below:

In certain embodiments, the present invention relates to compounds ofFormula (VIa), Formula (VIIb), Formula (VIIc), or Formula (VId), andpharmaceutically acceptable salts thereof, wherein R⁵ is an aryl orheteroaryl group derived from one of the following by removal of onehydrogen atom:

wherein each of the above shown groups is optionally substituted and isconnected to the pyrazole or triazole ring through a carbon atom or,where possible, a nitrogen atom.

In certain embodiments, the present invention relates to compounds ofany of the foregoing formulas, and pharmaceutically acceptable saltsthereof, wherein R⁵ is a heterocyclic group derived from one of thefollowing by removal of one hydrogen atom:

wherein each of the above shown groups is optionally substituted and isconnected to the pyrazole or triazole ring through a carbon atom or anitrogen atom. In certain embodiments, each of these groups is connectedto the pyrazole or triazole ring through a nitrogen atom. In certainembodiments, each of these groups is substituted with one or moresubstituents independently selected from C₁-C₆-alkyl, aryl, heteroaryl,C₃-C₆-cycloalkyl, spiro-C₁-C₆-cycloalkyl and fused C₁-C₆-cycloalkyl.

In certain embodiments, the present invention relates to compounds ofFormula (VIIa), Formula (VIIb), Formula (VIIc), or Formula (VIId), andpharmaceutically acceptable salts thereof, wherein R⁵ is -L-R¹²; whereinL is —O—, —N(R¹¹)C(O)—, —OC(O)N(R¹¹)—, —N(R¹¹)C(O)O—,—N(R¹¹)C(O)N(R¹¹)—, or —N(R¹¹)S(O)₂—; R¹¹ and R¹² are as previouslydefined.

In certain embodiments, the present invention relates to compounds ofFormula (VIIa), Formula (VIIb), Formula (VIIc), or Formula (VIId), andpharmaceutically acceptable salts thereof, wherein

is selected from the groups below:

wherein R¹⁰ and R¹¹ are as previously defined.

It will be appreciated that the description of the present inventionherein should be construed in congruity with the laws and principles ofchemical bonding. In some instances, it may be necessary to remove ahydrogen atom in order to accommodate a substituent at any givenlocation.

It will be yet appreciated that the compounds of the present inventionmay contain one or more asymmetric carbon atoms and may exist inracemic, diastereoisomeric, and optically active forms. It will still beappreciated that certain compounds of the present invention may exist indifferent tautomeric forms. All tautomers are contemplated to be withinthe scope of the present invention.

In one aspect, the compounds of the invention are useful in HBVtreatment by disrupting, accelerating, reducing, delaying and/orinhibiting normal viral core protein functions including, but notlimited to, direct or indirect interaction with viral relaxed circular(rc) DNA, cccDNA, or reverse transcriptase, direct or indirectinteraction with host proteins such as histones or host partners such askinase, capsid assembly and/or disassembly of immature or matureparticles, thereby inducing aberrant capsid morphology and leading toantiviral effects such as disruption of virion assembly and/ordisassembly, virion maturation, and/or virus egress. In one embodiment,a disruptor of capsid assembly interacts with mature or immature viralcapsid to perturb the stability of the capsid, thus affecting assemblyand/or disassembly. In another embodiment, a disruptor of capsidassembly perturbs protein folding and/or salt bridges required forstability, function and/or normal morphology of the viral capsid,thereby disrupting and/or accelerating capsid assembly and/ordisassembly. In yet another embodiment, the compounds of the inventionbind capsid and alter metabolism of cellular polyproteins andprecursors, leading to abnormal accumulation of protein monomers and/oroligomers and/or abnormal particles, which causes cellular toxicity anddeath of infected cells. In another embodiment, the compounds of theinvention cause failure of the formation of capsid of optimal stability,affecting efficient uncoating and/or disassembly of viruses (e.g.,during infectivity).

In one embodiment, the compounds of the invention disrupt and/oraccelerate capsid assembly and/or disassembly when the capsid protein isimmature. In another embodiment, the compounds of the invention disruptand/or accelerate capsid assembly and/or disassembly when the capsidprotein is mature. In yet another embodiment, the compounds of theinvention disrupt and/or accelerate capsid assembly and/or disassemblyduring vial infectivity. In yet another embodiment, the disruptionand/or acceleration of capsid assembly and/or disassembly attenuates HBVviral infectivity and/or reduces viral load. In yet another embodiment,disruption, acceleration, inhibition, delay and/or reduction of capsidassembly and/or disassembly eradicates the virus from the host organism.In yet another embodiment, the compounds of the invention disrupt and/ormodulate the interaction between core protein and viral rcDNA, cccDNA orreverse transcriptase during vial infectivity. In yet anotherembodiment, the compounds of the invention disrupt and/or modulate theinteraction between core protein and host partners or proteins duringvial infectivity. In yet another embodiment, eradication of the HBV froma host advantageously obviates the need for chronic long-term therapyand/or reduces the duration of long-term therapy.

In one embodiment, the compounds described herein are suitable formonotherapy and are effective against natural or native HBV strains andagainst HBV strains resistant to currently known drugs. In anotherembodiment, the compounds described herein are suitable for use incombination therapy.

In another embodiment, the compounds of the invention can be used inmethods of modulating (e.g., inhibit, disrupt or accelerate) theactivity of HBV cccDNA. In yet another embodiment, the compounds of theinvention can be used in methods of diminishing or preventing theformation of HBV cccDNA. In another embodiment, the additionaltherapeutic agent is selected from immune modulator or immune stimulatortherapies, which includes T-cell response activator AIC649 andbiological agents belonging to the interferon class, such as interferonalpha 2a or 2b or modified interferons such as pegylated interferon,alpha 2a, alpha 2b, lamda; or STING (stimulator of interferon genes)modulator; or TLR modulators such as TLR-7 agonists, TLR-8 agonists orTLR-9 agonists; or therapeutic vaccines to stimulate an HBV-specificimmune response such as virus-like particles composed of HBcAg andHBsAg, immune complexes of HBsAg and HBsAb, or recombinant proteinscomprising HBx, HBsAg and HBcAg in the context of a yeast vector; orimmunity activator such as SB-9200 of certain cellular viral RNA sensorssuch as RIG-I, NOD2, and MDA5 protein; or RNA interence (RNAi) or smallinterfering RNA (siRNA) such as ARC-520, ARC-521, ARB-1467, and ALN-HBVRNAi; or another core protein inhibitor or modulator; or antiviralagents that block viral entry or maturation or target the HBV polymerasesuch as nucleoside or nucleotide or non-nucleos(t)ide polymeraseinhibitors, and agents of distinct or unknown mechanism including agentsthat disrupt the function of other essential viral protein(s) or hostproteins required for HBV replication or persistence such as REP 2139and RG7834. In an embodiment of the combination therapy, the reversetranscriptase inhibitor is at least one of Zidovudine, Didanosine,Zalcitabine, ddA, Stavudine, Lamivudine, Aba-cavir, Emtricitabine,Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir,valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA,cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.

In another embodiment of the combination therapy, the TLR-7 agonist isselected from the group consisting of SM360320(9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)ad-enine), AZD 8848 (methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl] amino Imethyl)phenyl] acetate), GS-9620(4-Amino-2-butoxy-8-[3-(1-pyrrolidinylmethyl)benzyl]-7,8-dihydro-6(5H)-pteridinone),and RO6864018.

In another embodiment of the combination therapy, the TLR-8 agonist isGS-9688.

In an embodiment of these combination therapies, the compound and theadditional therapeutic agent are co-formulated. In another embodiment,the compound and the additional therapeutic agent are co-administered.

In another embodiment of the combination therapy, administering thecompound of the invention allows for administering of the additionaltherapeutic agent at a lower dose or frequency as compared to theadministering of the at least one additional therapeutic agent alonethat is required to achieve similar results in prophylactically treatingan HBV infection in an individual in need thereof.

In another embodiment of the combination therapy, before administeringthe therapeutically effective amount of the compound of the invention,the individual is known to be refractory to a compound selected from thegroup consisting of a HBV polymerase inhibitor, interferon, viral entryinhibitor, viral maturation inhibitor, distinct capsid assemblymodulator, antiviral compounds of distinct or unknown mechanism, andcombination thereof.

In still another embodiment of the method, administering the compound ofthe invention reduces viral load in the individual to a greater extentcompared to the administering of a compound selected from the groupconsisting of a HBV polymerase inhibitor, interferon, viral entryinhibitor, viral maturation inhibitor, distinct capsid assemblymodulator, antiviral compounds of distinct or unknown mechanism, andcombination thereof.

In another embodiment, administering of the compound of the inventioncauses a lower incidence of viral mutation and/or viral resistance thanthe administering of a compound selected from the group consisting of aHBV polymerase inhibitor, interferon, viral entry inhibitor, viralmaturation inhibitor, distinct capsid assembly modulator, antiviralcompounds of distinct or unknown mechanism, and combination thereof.

It should be understood that the compounds encompassed by the presentinvention are those that are suitably stable for use as pharmaceuticalagent.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system comprising at least one aromatic ring,including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system thatcomprises at least one aromatic ring. Polycyclic aryls can comprisefused rings, covalently attached rings or a combination thereof.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclicaromatic radical having one or more ring atom selected from S, O and N;and the remaining ring atoms are carbon, wherein any N or S containedwithin the ring may be optionally oxidized. Heteroaryl includes, but isnot limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fusedrings, covalently attached rings or a combination thereof.

In accordance with the invention, aromatic groups can be substituted orunsubstituted.

The term “bicyclic aryl” or “bicyclic heteroaryl” refers to a ringsystem consisting of two rings wherein at least one ring is aromatic;and the two rings can be fused or covalently attached.

The term “alkyl” as used herein, refers to saturated, straight- orbranched-chain hydrocarbon radicals. “C₁-C₃ alkyl,” “C₁-C₆ alkyl,”“C₁-C₁₀ alkyl” “C₂-C₄ alkyl,” or “C₃-C₆ alkyl,” refer to alkyl groupscontaining from one to three, one to six, one to ten carbon atoms, 2 to4 and 3 to 6 carbon atoms respectively. Examples of C₁-C₈ alkyl radicalsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.

The term “alkenyl” as used herein, refers to straight- or branched-chainhydrocarbon radicals having at least one carbon-carbon double bond bythe removal of a single hydrogen atom. “C₂-C₁₀ alkenyl,” “C₂-C₈alkenyl,” “C₂-C₄ alkenyl,” or “C₃-C₆ alkenyl,” refer to alkenyl groupscontaining from two to ten, two to eight, two to four or three to sixcarbon atoms respectively. Alkenyl groups include, but are not limitedto, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl,octenyl, and the like.

The term “alkynyl” as used herein, refers to straight- or branched-chainhydrocarbon radicals having at least one carbon-carbon triple bond bythe removal of a single hydrogen atom. “C₂-C₁₀ alkynyl,” “C₂-C₈alkynyl,” “C₂-C₄ alkynyl,” or “C₃-C₆ alkynyl,” refer to alkynyl groupscontaining from two to ten, two to eight, two to four or three to sixcarbon atoms respectively. Representative alkynyl groups include, butare not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl,and the like.

The term “cycloalkyl”, as used herein, refers to a monocyclic orpolycyclic saturated carbocyclic ring or a bi- or tri-cyclic groupfused, bridged or spiro system, and the carbon atoms may be optionallyoxo-substituted or optionally substituted with exocyclic olefinic,iminic or oximic double bond. Preferred cycloalkyl groups include C₃-C₁₂cycloalkyl, C₃-C₆ cycloalkyl, C₃-C₈ cycloalkyl and C₄-C₇ cycloalkyl.Examples of C₃-C₁₂ cycloalkyl include, but not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl,4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl,spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, andthe like.

The term “cycloalkenyl”, as used herein, refers to monocyclic orpolycyclic carbocyclic ring or a bi- or tri-cyclic group fused, bridgedor spiro system having at least one carbon-carbon double bond and thecarbon atoms may be optionally oxo-substituted or optionally substitutedwith exocyclic olefinic, iminic or oximic double bond. Preferredcycloalkenyl groups include C₃-C₁₂ cycloalkenyl, C₃-C₈ cycloalkenyl orC₅-C₇ cycloalkenyl groups. Examples of C₃-C₁₂ cycloalkenyl include, butnot limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl,bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-1-enyl,bicyclo[4.2.1]non-3-en-9-yl, and the like.

As used herein, the term “arylalkyl” means a functional group wherein analkylene chain is attached to an aryl group, e.g., —CH₂CH₂-phenyl. Theterm “substituted arylalkyl” means an arylalkyl functional group inwhich the aryl group is substituted. Similarly, the term“heteroarylalkyl” means a functional group wherein an alkylene chain isattached to a heteroaryl group. The term “substituted heteroarylalkyl”means a heteroarylalkyl functional group in which the heteroaryl groupis substituted.

As used herein, the term “alkoxy” employed alone or in combination withother terms means, unless otherwise stated, an alkyl group having thedesignated number of carbon atoms connected to the rest of the moleculevia an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy,2-propoxy (isopropoxy) and the higher homologs and isomers. Preferredalkoxy are (C₁-C₃) alkoxy.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclic and cycloalkenyl moiety described herein can also be analiphatic group or an alicyclic group.

An “aliphatic” group is a non-aromatic moiety comprised of anycombination of carbon atoms, hydrogen atoms, halogen atoms, oxygen,nitrogen or other atoms, and optionally contains one or more units ofunsaturation, e.g., double and/or triple bonds. Examples of aliphaticgroups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH,NH, NH₂, C(O), S(O)₂, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH₂, S(O)₂NH,S(O)₂NH₂, NHC(O)NH₂, NHC(O)C(O)NH, NHS(O)₂NH, NHS(O)₂NH₂, C(O)NHS(O)₂,C(O)NHS(O)₂NH or C(O)NHS(O)₂NH₂, and the like, groups comprising one ormore functional groups, non-aromatic hydrocarbons (optionallysubstituted), and groups wherein one or more carbons of a non-aromatichydrocarbon (optionally substituted) is replaced by a functional group.Carbon atoms of an aliphatic group can be optionally oxo-substituted. Analiphatic group may be straight chained, branched, cyclic, or acombination thereof and preferably contains between about 1 and about 24carbon atoms, more typically between about 1 and about 12 carbon atoms.In addition to aliphatic hydrocarbon groups, as used herein, aliphaticgroups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls,such as polyalkylene glycols, polyamines, and polyimines, for example.Aliphatic groups may be optionally substituted.

The terms “heterocyclic” or “heterocycloalkyl” can be usedinterchangeably and referred to a non-aromatic ring or a bi- ortri-cyclic group fused, bridged or spiro system, where (i) each ringsystem contains at least one heteroatom independently selected fromoxygen, sulfur and nitrogen, (ii) each ring system can be saturated orunsaturated (iii) the nitrogen and sulfur heteroatoms may optionally beoxidized, (iv) the nitrogen heteroatom may optionally be quaternized,(v) any of the above rings may be fused to an aromatic ring, and (vi)the remaining ring atoms are carbon atoms which may be optionallyoxo-substituted or optionally substituted with exocyclic olefinic,iminic or oximic double bond. Representative heterocycloalkyl groupsinclude, but are not limited to, 1,3-dioxolane, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, quinoxalinyl, pyridazinonyl,2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl,5-azaspiro[2.5]octyl, 1-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl,and tetrahydrofuryl. Such heterocyclic groups may be furthersubstituted. Heteroaryl or heterocyclic groups can be C-attached orN-attached (where possible).

It is understood that any alkyl, alkenyl, alkynyl, alicyclic,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphaticmoiety or the like, described herein can also be a divalent ormultivalent group when used as a linkage to connect two or more groupsor substituents, which can be at the same or different atom(s). One ofskill in the art can readily determine the valence of any such groupfrom the context in which it occurs.

The term “substituted” refers to substitution by independent replacementof one, two, or three or more of the hydrogen atoms with substituentsincluding, but not limited to, deuterium, tritium, —F, —Cl, —Br, —I,—OH, C₁-C₁₂-alkyl; C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl, protected hydroxy,—NO₂, —N₃, —CN, —NH₂, protected amino, oxo, thioxo, —NH—C₁-C₁₂-alkyl,—NH—C₂-C₈-alkenyl, —NH—C₂-C₈-alkynyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl,—NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino,-diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₈-alkenyl, —O—C₂-C₈-alkynyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O— heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₈-alkenyl, —C(O)—C₂-C₈-alkynyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₈-alkenyl,—CONH—C₂-C₈-alkynyl, —CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl,—CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl,—OCO₂—C₂-C₈-alkenyl, —OCO₂—C₂-C₈-alkynyl, —OCO₂—C₃-C₁₂-cycloalkyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —CO₂—C₁-C₁₂ alkyl,—CO₂—C₂-C₈ alkenyl, —CO₂—C₂-C₈ alkynyl, CO₂—C₃-C₁₂-cycloalkyl, —CO₂—aryl, CO₂-heteroaryl, CO₂-heterocyloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₈-alkenyl, —OCONH—C₂-C₈-alkynyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH— heterocyclo-alkyl, —NHC(O)H,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₈-alkenyl, —NHC(O)—C₂-C₈-alkynyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocyclo-alkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₈-alkenyl,—NHCO₂— C₂-C₈-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂— heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₈-alkenyl,—NHC(O)NH—C₂-C₈-alkynyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₈-alkenyl,—NHC(S)NH—C₂-C₈-alkynyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₈-alkenyl,—NHC(NH)NH—C₂-C₈-alkynyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl,—NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₈-alkenyl, —NHC(NH)—C₂-C₈-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₈-alkenyl, —C(NH)NH—C₂-C₈-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₈-alkenyl,—S(O)—C₂-C₈-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl, —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₈-alkenyl, —SO₂NH— C₂-C₈-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH— heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₈-alkenyl, —NHSO₂—C₂-C₈-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₈-alkenyl, —S—C₂-C₈-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl,methylthiomethyl, or -L′-R′, wherein L′ is C₁-C₆alkylene,C₂-C₆alkenylene or C₂-C₆alkynylene, and R′ is aryl, heteroaryl,heterocyclic, C₃-C₁₂cycloalkyl or C₃-C₁₂cycloalkenyl. In certainembodiments, the substituents are independently selected from halo,preferably Cl and F; C₁-C₄-alkyl, preferably methyl and ethyl;halo-C₁-C₄-alkyl, such as fluoromethyl, difluoromethyl, andtrifluoromethyl; C₂-C₄-alkenyl; halo-C₂-C₄-alkenyl; C₃-C₆-cycloalkyl,such as cyclopropyl; C₁-C₄-alkoxy, such as methoxy and ethoxy;halo-C₁-C₄-alkoxy, such as fluoromethoxy, difluoromethoxy, andtrifluoromethoxy, —CN; —OH; NH₂; C₁-C₄-alkylamino; di(C₁-C₄-alkyl)amino;and NO₂. It is understood that the aryls, heteroaryls, alkyls, and thelike can be further substituted. In some cases, each substituent in asubstituted moiety is additionally optionally substituted when possiblewith one or more groups, each group being independently selected fromC₁-C₄-alkyl; —CF₃, —OCH₃, —OCF₃, —F, —Cl, —Br, —I, —OH, —NO₂, —CN, and—NH₂. Preferably, a substituted alkyl group, such as a substitutedmethyl group, is substituted with one or more halogen atoms, morepreferably one or more fluorine or chlorine atoms.

The term “halo” or “halogen” alone or as part of another substituent, asused herein, refers to a fluorine, chlorine, bromine, or iodine atom.

The term “optionally substituted”, as used herein, means that thereferenced group may be substituted or unsubstituted. In one embodiment,the referenced group is optionally substituted with zero substituents,i.e., the referenced group is unsubstituted. In another embodiment, thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from groups describedherein.

The term “hydrogen” includes hydrogen and deuterium. In addition, therecitation of an atom includes other isotopes of that atom so long asthe resulting compound is pharmaceutically acceptable.

In certain embodiments, the compounds of each formula herein are definedto include isotopically labelled compounds. An “isotopically labelledcompound” is a compound in which at least one atomic position isenriched in a specific isotope of the designated element to a levelwhich is significantly greater than the natural abundance of thatisotope. For example, one or more hydrogen atom positions in a compoundcan be enriched with deuterium to a level which is significantly greaterthan the natural abundance of deuterium, for example, enrichment to alevel of at least 1%, preferably at least 20% or at least 50%. Such adeuterated compound may, for example, be metabolized more slowly thanits non-deuterated analog, and therefore exhibit a longer half-life whenadministered to a subject. Such compounds can synthesize using methodsknown in the art, for example by employing deuterated startingmaterials. Unless stated to the contrary, isotopically labelledcompounds are pharmaceutically acceptable.

The term “hydroxy activating group,” as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxyl groupso that it will depart during synthetic procedures such as in asubstitution or an elimination reaction. Examples of hydroxyl activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxyl,” as used herein, refers to a hydroxy groupactivated with a hydroxyl activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theart are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl,chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl,methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl,benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl,benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl,trimethylsilyl, triisopropylsilyl, and the like.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy prodrug group,” as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992) and in “Prodrugs of Alcohols and Phenols” by S. S. Dhareshwar andV. J. Stella, in Prodrugs Challenges and Rewards Part-2, (Biotechnology:Pharmaceutical Aspects), edited by V. J. Stella, et al, Springer andAAPSPress, 2007, pp 31-99.

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the artare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of amino protecting groups include, but are not limitedto, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl,benzyloxycarbonyl, and the like.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “amino acid” refers to naturally occurring and synthetic α, β,γ, or δ amino acids, and includes but is not limited to, amino acidsfound in proteins or intermediates in metabolism of amino acids orproteins, i.e. glycine, alanine, valine, leucine, isoleucine,methionine, phenylalanine, tryptophan, proline, serine, threonine,cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine,citrulline, arginine and histidine. In certain embodiments, the aminoacid is in the L-configuration. In certain embodiments, the amino acidis in the D-configuration. In certain embodiments, the amino acid isprovided as a substituent of a compound described herein, wherein theamino acid is a residue selected from the group consisting of alanyl,valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl,methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl,asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl,histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleuccinyl, β-prolinyl,β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl,β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl,β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl and β-histidinyl.

The term “amino acid derivative” refers to a group derivable from anaturally or non-naturally occurring amino acid, as described andexemplified herein. Amino acid derivatives are apparent to those ofskill in the art and include, but are not limited to, ester, aminoalcohol, amino aldehyde, amino lactone, and N-methyl derivatives ofnaturally and non-naturally occurring amino acids. In an embodiment, anamino acid derivative is provided as a substituent of a compounddescribed herein, wherein the substituent is —NR^(u)-G(S_(c))—C(O)-Q¹,wherein Q¹ is —SR^(v), —NR^(v)R^(v) or alkoxyl, R^(v) is hydrogen oralkyl, S_(c) is a side-chain of a naturally occurring or non-naturallyoccurring amino acid, G is C₁-C₂ alkyl, and R^(u) is hydrogen; or R^(u)and S_(c) are taken together with the atoms to which they are attachedto form a five-membered heterocyclic ring. In an embodiment, an aminoacid derivative is provided as a substituent of a compound describedherein, wherein the substituent is —O—C(O)-G(S_(c))—NH-Q², wherein Q² ishydrogen or alkoxyl, S_(c) is a side-chain of a naturally occurring ornon-naturally occurring amino acid and G is C₁-C₂ alkyl. In certainembodiments, Q² and S_(c) are taken together with the atoms to whichthey are attached to form a five-membered heterocyclic ring. In certainembodiments, G is an optionally substituted methylene and S_(c) isselected from the group consisting of hydrogen, alkyl, arylalkyl,heterocycloalkyl, carboxylalkyl, heteroarylalkyl, aminoalkyl,hydroxylalkyl, aminoiminoaminoalkyl, aminocarbonylalkyl, sulfanylalkyl,carbamoylalkyl, alkylsulfanylalkyl and hydroxylarylalkyl. In anembodiment, an amino acid derivative is provided as a substituent of acompound described herein, wherein the amino acid derivative is in theD-configuration. In an embodiment, an amino acid derivative is providedas a substituent of a compound described herein, wherein the amino acidderivative is in the L-configuration.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include chloro, bromo and iodogroups; sulfonic ester groups, such as mesylate, tosylate, brosylate,nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, N Y, 1986.

The term “protic solvent,” as used herein, refers to a solvent thattends to provide protons, such as an alcohol, for example, methanol,ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Suchsolvents are well known to those skilled in the art, and it will beobvious to those skilled in the art that individual solvents or mixturesthereof may be preferred for specific compounds and reaction conditions,depending upon such factors as the solubility of reagents, reactivity ofreagents and preferred temperature ranges, for example. Furtherdiscussions of protogenic solvents may be found in organic chemistrytextbooks or in specialized monographs, for example: Organic SolventsPhysical Properties and Methods of Purification, 4th ed., edited by JohnA. Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, N Y, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable,” as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the invention will be evident to those of ordinary skill inthe art. Additionally, the various synthetic steps may be performed inan alternate sequence or order to give the desired compounds. Syntheticchemistry transformations and protecting group methodologies (protectionand deprotection) useful in synthesizing the compounds described hereinare known in the art and include, for example, those such as describedin R. Larock, Comprehensive Organic Transformations, 2^(nd) Ed.Wiley-VCH (1999); T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M.Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wileyand Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995), and subsequent editionsthereof.

The term “subject,” as used herein, refers to an animal. Preferably, theanimal is a mammal. More preferably, the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. Tautomers may be incyclic or acyclic. The configuration of any carbon-carbon double bondappearing herein is selected for convenience only and is not intended todesignate a particular configuration unless the text so states; thus acarbon-carbon double bond or carbon-heteroatom double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion.

Certain compounds of the present invention may also exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present invention includes each conformationalisomer of these compounds and mixtures thereof.

As used herein, the term “pharmaceutically acceptable salt,” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts are saltsof an amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentane-propionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, esters ofC₁-C₆-alkanoic acids, such as acetate, propionate, butyrate and pivalateesters.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intra-arterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose, any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectable.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to Van Devanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of whichare incorporated herein by reference).

Antiviral Activity

An inhibitory amount or dose of the compounds of the present inventionmay range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively fromabout 1 to about 50 mg/Kg. Inhibitory amounts or doses will also varydepending on route of administration, as well as the possibility ofco-usage with other agents.

According to the methods of treatment of the present invention, viralinfections, conditions are treated or prevented in a patient such as ahuman or another animal by administering to the patient atherapeutically effective amount of a compound of the invention, in suchamounts and for such time as is necessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg. Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the present invention described herein can, forexample, be administered by injection, intravenously, intra-arterial,subdermally, intraperitoneally, intramuscularly, or subcutaneously; ororally, buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with pharmaceutically excipients or carriers toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations may contain from about 20% to about 80% activecompound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

When the compositions of this invention comprise a combination of acompound of the Formula described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

The said “additional therapeutic or prophylactic agents” includes butnot limited to, immune therapies (eg. interferon), therapeutic vaccines,antifibrotic agents, anti-inflammatory agents such as corticosteroids orNSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines(e.g. theophylline), mucolytic agents, anti-muscarinics,anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists),anti-oxidants (e.g. N-acetylcysteine), cytokine agonists, cytokineantagonists, lung surfactants and/or antimicrobial and anti-viral agents(e.g. ribavirin and amantidine). The compositions according to theinvention may also be used in combination with gene replacement therapy.

Combination and Alternation Therapy for HBV

It has been recognized that drug-resistant variants of HIV, HBV and HCVcan emerge after prolonged treatment with an antiviral agent. Drugresistance most typically occurs by mutation of a gene that encodes fora protein such as an enzyme used in viral replication, and mosttypically in the case of HIV, reverse transcriptase, protease, or DNApolymerase, and in the case of HBV, DNA polymerase, or in the case ofHCV, RNA polymerase, protease, or helicase. Recently, it has beendemonstrated that the efficacy of a drug against HIV infection can beprolonged, augmented, or restored by administering the compound incombination or alternation with a second, and perhaps third, antiviralcompound that induces a different mutation from that caused by theprinciple drug. The compounds can be used for combinations and areselected from the group consisting of a HBV polymerase inhibitor,interferon, TLR modulators such as TLR-7 agonists or TLR-9 agonists,therapeutic vaccines, immune activator of certain cellular viral RNAsensors, viral entry inhibitor, viral maturation inhibitor, distinctcapsid assembly modulator, antiviral compounds of distinct or unknownmechanism, and combination thereof. Alternatively, the pharmacokinetics,biodistribution, or other parameter of the drug can be altered by suchcombination or alternation therapy. In general, combination therapy istypically preferred over alternation therapy because it induces multiplesimultaneous stresses on the virus.

Preferred compounds for combination or alternation therapy for thetreatment of HBV include 3TC, FTC, L-FMAU, interferon, adefovirdipivoxil, entecavir, telbivudine (L-dT), valtorcitabine (3′-valinylL-dC), β-D-dioxolanyl-guanine (DXG), β-D-dioxolanyl-2,6-diaminopurine(DAPD), and β-D-dioxolanyl-6-chloropurine (ACP), famciclovir,penciclovir, lobucavir, ganciclovir, and ribavirin.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are: Ac for acetyl; AcOH for acetic acid; AIBNfor azobisisobutyronitrile; BINAP for2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc₂O fordi-tert-butyl-dicarbonate; Boc for t-butoxycarbonyl; Bpoc for1-methyl-1-(4-biphenylyl)ethyl carbonyl; Bz for benzoyl; Bn for benzyl;BocNHOH for tert-butyl N-hydroxycarbamate; t-BuOK for potassiumtert-butoxide; Bu₃SnH for tributyltin hydride; BOP for(benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumHexafluorophosphate; Brine for sodium chloride solution in water; BSAfor N,O-bis-(trimethylsilyl)acetamide; CDI for carbonyldiimidazole;CH₂Cl₂ and DCM for dichloromethane; CH₃ for methyl; CH₃CN foracetonitrile; Cs₂CO₃ for cesium carbonate; CuCl for copper (I) chloride;CuI for copper (I) iodide; dba for dibenzylidene acetone; dppb fordiphenylphos-phinobutane; DBU for 1,8-diazabicyclo[5.4.0]-undec-7-ene;DCC for N,N′-dicyclohexyl-carbodiimide; DEAD fordiethylazodicarboxylate; DIAD for diisopropyl azodicarboxylate; DIPEA or(i-Pr)₂EtN for N,N,-diisopropylethyl amine; Dess-Martin periodinane for1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-β-(1H)-one; DMAP for4-dimethylamino-pyridine; DME for 1,2-dimethoxyethane; DMF forN,N-dimethylformamide; DMSO for dimethyl sulfoxide; DMT fordi(p-methoxyphenyl)-phenylmethyl or dimethoxytrityl; DPPA fordiphenylphosphoryl azide; EDC forN—(β-dimethylaminopropyl)-N′-ethylcarbodiimide; EDC HCl forN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; EtOAc forethyl acetate; EtOH for ethanol; Et₂O for diethyl ether; HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluroniumHexafluoro-phosphate; HCl for hydrogen chloride; HOBT for1-hydroxybenzotriazole; K₂CO₃ for potassium carbonate; n-BuLi forn-butyl lithium; i-BuLi for i-butyl lithium; t-BuLi for t-butyl lithium;PhLi for phenyl lithium; LDA for lithium diisopropylamide; LiTMP forlithium 2,2,6,6-tetramethyl-piperidinate; MeOH for methanol; Mg formagnesium; MOM for methoxymethyl; Ms for mesyl or —SO₂—CH₃; Ms₂O formethanesulfonic anhydride or mesyl-anhydride; MTBE for t-butyl methylether; NaN(TMS)₂ for sodium bis(trimethylsilyl)amide; NaCl for sodiumchloride; NaH for sodium hydride; NaHCO₃ for sodium bicarbonate orsodium hydrogen carbonate; Na₂CO₃ for sodium carbonate; NaOH for sodiumhydroxide; Na₂SO₄ for sodium sulfate; NaHSO₃ for sodium bisulfite orsodium hydrogen sulfite; Na₂S₂O₃ for sodium thiosulfate; NH₂NH₂ forhydrazine; NH₄HCO₃ for ammonium bicarbonate; NH₄C₁ for ammoniumchloride; NMO for N-methyl-morpholine N-oxide; NaIO₄ for sodiumperiodate; Ni for nickel; NSFI for N-fluorobenzene-sulfonimide; OH forhydroxyl; o/n for overnight; OsO₄ for osmium tetroxide; PTSA forp-toluenesulfonic acid; PPTS for pyridinium p-toluenesulfonate; TBAF fortetrabutyl-ammonium fluoride; TEA or Et₃N for triethylamine; TES fortriethylsilyl; TESCl for triethylsilyl chloride; TESOTf fortriethylsilyl trifluoro-methanesulfonate; TFA for trifluoroacetic acid;THF for tetrahydro-furan; TMEDA forN,N,N′,N′-tetramethylethylene-diamine; TPP or PPh₃ fortriphenyl-phosphine; Troc for 2,2,2-trichloroethyl carbonyl; Ts fortosyl or —SO₂—C₆H₄CH₃; Ts₂O for tolylsulfonic anhydride ortosyl-anhydride; TsOH for p-tolylsulfonic acid; Pd for palladium; Ph forphenyl; POPd for dihydrogendichlorobis(di-tert-butylphosphinito-κP)palladate(II); Pd₂(dba)₃ fortris(dibenzylideneacetone) dipalladium (0); Pd(PPh₃)₄ fortetrakis(triphenyl-phosphine)palladium (0); PdCl₂(PPh₃)₂ fortrans-dichlorobis-(triphenylphosphine)palladium (II); Pt for platinum;Rh for rhodium; rt for room temperature; Ru for ruthenium; SFC forsupercritical fluid chromatography; TBS for tert-butyl dimethylsilyl;TMS for trimethylsilyl; or TMSCl for trimethylsilyl chloride.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared. These schemes are of illustrative purpose, and are not meantto limit the scope of the invention. Equivalent, similar, or suitablesolvents, reagents or reaction conditions may be substituted for thoseparticular solvents, reagents, or reaction conditions described hereinwithout departing from the general scope of the method of synthesis.Certain reactions can be conducted as generally described in WO2017/011160, WO 2017/011162, and WO 2017/011163.

The compounds of Formula I may be prepared via several differentsynthetic routes from a variety of optionally substituted phenyl,heteroaryl, or fused bicyclic aryl or heteroaryl precursors using thechemical transformations that are known to those skilled in the art. Ageneral synthetic strategy is shown in Scheme 1. For example anintermediate 1-1 where X is a leaving group, such as a halogen, and Pgis a protecting group, such as Boc or benzyl, can be coupled to anucleophile 1-2. The nature of the coupling depends on the identity ofR⁵. For example if R⁵ is aryl or heteroaryl, then Q could be boron, tin,or zinc and the reaction could be catalyzed by palladium to give thedesired product 1-3. Alternatively, if R⁵ is a nucleophilic nitrogen andQ could be hydrogen, then copper catalyzed compling would giveintermediate 1-3. To continue the reaction sequence the Pg would beremoved from intermediate 1-3 followed by coupling with electrophile 1-4where Lg is a leaving group, such as phenol, to give desired compound1-5.

Alternatively, as shown in Scheme 2, intermediate 2-1, could react withelectrophile 2-2, to give intermediate 2-3. Coupling betweenintermediate 2-3 and nucleophile 2-4 would give desired compound 2-5.

As shown in Scheme 3, an intermediate 3-5 corresponding to relatedintermediates shown above could be synthesized as follows. Reductiveamination between amine 3-1 and aldehyde 3-2 followed by treatment withboc anhydride, would give with boc-protected amine 3-3. Formation of themesylate with MsCl followed by treatment with a strong base such assodium hydride would give intermediate 3-4, which upon treatment with anelectrophilic halogen source such as NBS or NIS would give intermediate3-5, where X is bromine or iodine respectively.

Alternatively, diol 4-1 could be activated with thionyl chloride thenoxidized with RuCl3 and sodium periodate to give compound 4-2.Nucleophilic displacement with pyrazole under basic conditions couldgive intermediate 4-3. Conversion of the alcohol could occur viaMitsunobu reaction with phthalamide, followed by liberation of the freeamine with hydrazine and protection as the benzyl amine via reductiveamination with benzaldehyde to give intermediate 4-4. Condensation withaldehyde 4-5 under acidic conditions could give intermediate 4-6 whichcould be utilized as above.

Alternatively, ketone 5-1, where Pg is a protecting group such as Boc,can be deprotonated with a strong base such as LHMDS and treated with anacyl chloride 5-2 to give intermediate 5-3. Treatment with hydrazinewould give pyrazole 5-4. Removal of the protecting group would giverintermediate 5-5 which could be elaborated as shown above.

As shown in Scheme 6, an intermediate 6-5 corresponding to relatedintermediates shown above could be synthesized as follows. Reductiveamination between amine 6-1 and benzaldehyde followed by alkylation withpropargyl bromide would give amine 6-2. Treatment of alcohol 6-2 withthionyl chloride would give alkyl chloride 6-3. Addition of sodium azideat elevated temperature would give an azide intermediate that could withwould then undergo [3+2] cycloaddition to give triazole 6-4, which upontreatment with an electrophilic halogen source such as NBS or NIS wouldgive intermediate 6-5, where X is bromine or iodine respectively.

It will be appreciated that, with appropriate manipulation andprotection of any chemical functionality, synthesis of compounds ofFormula I is accomplished by methods analogous to those above and tothose described in the Experimental section. Suitable protecting groupscan be found, but are not restricted to, those found in T W Greene and PG M Wuts “Protective Groups in Organic Synthesis”, 3rd Ed (1999), JWiley and Sons.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1

Step 1a.

A suspension of (1R,2R)-2-aminocyclopentan-1-ol hydrochloride (1.718 g,12.49 mmol) and 1H-pyrazole-5-carbaldehyde (1 g, 10.41 mmol), and sodiumbicarbonate (1.049 g, 12.49 mmol) in MeOH (52.0 ml) was stirred for 1 h.The reaction mixture was cooled to 0° C. followed by addition of sodiumborohydride (0.472 g, 12.49 mmol). The reaction was stirred for 30minutes followed by careful addition of water (52.0 ml) andBoc-anhydride (2.90 ml, 12.49 mmol). The reaction was stirred for 18 h.The reaction mixture was concentrated under vaccum. The reaction mixturewas diluted with EtOAc and washed with brine. The organic layer wasdried with Na₂SO₄, filtered and concentrated. The crude productchromatographed (silica, methanol/dichloromethane) to give the desiredcompound (0.78 g, 2.77 mmol, 27% yield) as a yellow oil that crystalizedupon standing.

Step 1b.

To a suspension of the compound from step 1a (0.78 g, 2.77 mmol) andEt₃N (1.16 mL, 8.32 mmol) in DCM (7.8 mL) at 0° C. was added mesylchloride (0.324 mL, 4.16 mmol). The reaction mixture was warmed to rtand stirred for 1 h. The reaction was extracted with DCM, washed withwater and brine. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The desired product was used without further purification(0.95 g, 96%).

Step 1c.

To a solution of compound from step 1b (0.95 g, 2.65 mmol) in DMF (8.8mL) at 0° C. was added sodium hydride (127 mg, 3.18 mmol, 60%). Thereaction mixture was warmed to rt and stirred for 18 h. The reactionmixture was diluted with EtOAc then washed with sat. NH₄C₁, water, andbrine. The organic layer was dried with Na₂SO₄, filtered andconcentrated. The crude product chromatographed (silica,methanol/dichloromethane) to give the desired compound (280 mg, 1.063mmol, 40% yield).

Step 1d.

To a solution of compound from step 1c (280 mg, 1.063 mmol) inacetonitrile (3.5 mL) was added N-iodosuccinimide (359 mg, 1.595 mmol).The reaction mixture was stirred for 1 h. The reaction mixture wasdiluted with EtOAc then washed with sat. aqueous Na₂S₂O₃, water, andbrine. The organic layer was dried with Na₂SO₄, filtered andconcentrated. The crude product chromatographed (silica,methanol/dichloromethane) to give the desired compound (380 mg, 0.976mmol, 92% yield).

Step 1e.

To a solution of compound from step 1d (190 mg, 0.488 mmol) and(4-fluorophenyl)boronic acid (102 mg, 0.732) in dioxane (1.3 mL) andwater (0.3 mL) was added K₂CO₃ (202 mg, 1.464 mmol) and Pd(PPh₃)₄ (28mg, 0.024 mmol). The reaction mixture was stirred at 80° C. for 18 h.The reaction mixture was diluted with EtOAc then washed with sat.aqueous Na₂S₂O₃, water, and brine. The organic layer was dried withNa₂SO₄, filtered and concentrated. The crude product chromatographed(silica, methanol/dichloromethane) to give the desired compound (170 mg,0.476 mmol, 97% yield).

Step 1f.

To a solution of compound from step 1e (170 mg, 0.476 mmol) in DCM (2mL) was added TFA (0.5 mL, 6.49 mmol). The reaction mixture was stirredat rt for 3 h then concentrated under vacuum. The desired product wasused without further purification.

Step 1g.

A solution of compound from step 1f (40 mg, 0.155 mmol), Et₃N (60 μL,0.466 mmol) and phenyl (3,4,5-trifluorophenyl)carbamate (50 mg, 0.187mmol) in DMF (1.5 mL) was stirred for 1 h. The crude reaction mixturewas purified via prep-HPLC (C18, acetonitrile/water) to give the titlecompound (6 mg, 9%). ESI-MS m/z=429.13, 430.14 [M−H]⁻.

Example 2

A solution of compound from step 1f (40 mg, 0.155 mmol), Et₃N (60 μL,0.466 mmol) and phenyl (3,4-difluorophenyl)carbamate (50 mg, 0.187 mmol)in DMF (1.5 mL) was stirred for 1 h. The crude reaction mixture waspurified via prep-HPLC (C18, acetonitrile/water) to give the titlecompound (10 mg, 16%). ESI-MS m/z=411.14 [M−H]⁻.

Example 3

A solution of compound from step 1f (40 mg, 0.155 mmol), Et₃N (60 μL,0.466 mmol) and phenyl (3-chloro-4-fluorophenyl)carbamate (50 mg, 0.187mmol) in DMF (1.5 mL) was stirred for 1 h. The crude reaction mixturewas purified via prep-HPLC (C18, acetonitrile/water) to give the titlecompound (8 mg, 12%). ESI-MS m/z=427.11, 429.11 [M−H]⁻.

Example 4

Step 4a.

To a suspension of compound from step 1d (190 mg, 0.488 mmol), K₂CO₃(202 mg, 1.464 mmol), and CuI (18.6 mg, 0.098 mmol) in DMSO (1.6 mL) wasadded trans-N,N′-dimethylcyclohexane-1,2-diamine (15 μL, 0.098 mmol) andisothiazolidinone 1,1-dioxide (67 μL, 0.732 mmol). The reaction mixturewas stirred at 80° C. for 18 h. The reaction mixture was diluted withEtOAc then washed with sat. aqueous Na₂S₂O₃, water, and brine. Theorganic layer was dried with Na₂SO₄, filtered and concentrated. Thecrude product chromatographed (silica, methanol/dichloromethane) to givethe desired compound (115 mg, 0.301 mmol, 62% yield).

Step 4b.

To a solution of compound from step 4a (115 mg, 0.301 mmol) in DCM (2mL) was added TFA (0.5 mL, 6.49 mmol). The reaction mixture was stirredat rt for 3 h then concentrated under vacuum. The desired product wasused without further purification.

Step 4c.

A solution of compound from step 4b (30 mg, 0.106 mmol), Et₃N (44 μL,0.127 mmol) and phenyl (3,4,5-trifluorophenyl)carbamate (32 mg, 0.127mmol) in DMF (1.5 mL) was stirred for 1 h. The crude reaction mixturewas purified via prep-HPLC (C18, acetonitrile/water) to give the titlecompound (9 mg, 19%). ESI-MS m/z=454.12[M−H]⁻.

Example 13

Step 13a.

The desired compound was prepared from the compound of example 1following a procedure similar to that described in steps 1a-1d, ESI-MSm/z=390.08 [M+H]⁺.

Step 13b.

To a mixture of compound from step 13a (63 mg, 0.162 mmol),thiazol-4-ylboronic acid (20.87 mg, 0.162 mmol), K₂CO₃ (67.1 mg, 0.486mmol) in dioxane (2 mL) and water (0.4 mL) was added Pd(PPh₃)₄ (21 mg,0.018 mmol) under N₂. The mixture was stirred at 80° C. for 15 h. Thereaction mixture was diluted with EtOAc then washed with sat. aqueousNa₂S₂O₃, water, and brine. The organic layer was dried with Na₂SO₄,filtered and concentrated. The crude product chromatographed (silica,methanol/dichloromethane) to give the desired compound (40.0 mg, 71%).

Step 13c.

To a solution of compound from step 13b (70 mg, 0.202 mmol) in DCM (2mL) was added TFA (0.08 mL, 1.01 mmol). The reaction mixture was stirredat rt for 2 h then concentrated under vacuum. The desired product wasused without further purification.

Step 13d.

A solution of compound from step 13c (24 mg, 0.097 mmol), Et₃N (41 μL,0.292 mmol) and phenyl (3,4,5-trifluorophenyl)carbamate (26 mg, 0.097mmol) in DMF (2 mL) was stirred for 10 h. The crude reaction mixture waspurified via prep-HPLC (C18, acetonitrile/water) to give the titlecompound (6.2 mg, 15%). ESI-MS m/z=420.29 [M+H]⁺.

Example 14

A solution of compound from step 13a (24 mg, 0.097 mmol), Et₃N (41 μL,0.292 mmol) and phenyl (3,4-difluorophenyl)carbamate (24.3 mg, 0.097mmol) in DMF (2 mL) was stirred for 10 h. The crude reaction mixture waspurified via prep-HPLC (C18, acetonitrile/water) to give the titlecompound (6.5 mg, 17%). ESI-MS m/z=402.29 [M+H]⁺.

Example 15

Step 15a.

To a suspension of compound from step 13a (270 mg, 0.694 mmol), K₃PO₄(14.72 mg, 0.069 mmol), and CuI (13.2 mg, 0.069 mmol) in dioxane (3 mL)was added trans-N,N′-dimethylcyclohexane-1,2-diamine (10.9 μL, 0.069mmol) and (S)-4,5,5-trimethyloxazolidin-2-one (90 mg, 0.694 mmol). Thereaction mixture was stirred at 100° C. for 16 h. The reaction mixturewas diluted with EtOAc then washed with sat. aqueous Na₂S₂O₃, water, andbrine. The organic layer was dried with Na₂SO₄, filtered andconcentrated. The crude product chromatographed (silica,methanol/dichloromethane) to give the desired compound (100 mg, 37%).

Step 15b.

To a solution of compound from step 15a (100 mg, 0.256 mmol) in DCM (2mL) was added TFA (59 μL, 0.768 mmol). The reaction mixture was stirredat rt for 3 h then concentrated under vacuum. The desired product wasused without further purification.

Step 15c.

A solution of compound from step 15b (24.5 mg, 0.084 mmol), Et₃N (35 μL,0.253 mmol) and phenyl (3,4,5-trifluorophenyl)carbamate (22.6 mg, 0.084mmol) in DMF (2 mL) was stirred for 6 h. The crude reaction mixture waspurified via prep-HPLC (C18, acetonitrile/water) to give the titlecompound (15 mg, 38%). ESI-MS m/z=464.20 [M+H]⁺.

Example 16

Step 16a.

Into a suspension of (1-aminocyclopropyl)methanol hydrochloride (0.371g, 3.0 mmol), 1H-pyrazole-5-carbaldehyde (0.241 g, 2.5 mmol) and MgSO4(2.2 g, 18 mmol) in CH₂Cl₂ (5.0 ml), trimethylamine (0.84 mL, 6.0 mmol)was added at rt and stirred o/n. The solid was collected under vacuumand washed with CH₂Cl₂ (10.0 ml). The collected solid was suspended inEtOH (6 mL) and MeOH (3 mL), and cooled to 0° C. followed by addition ofsodium borohydride (60% w/w, 0.16 g, 2.5 mmol). The reaction was stirredfor one hour followed by careful addition of water (5.0 ml), then Boc₂O(0.66 g, 3 mmol). It was stirred ar rt o/n and concentrated. The mixturewas diluted with EtOAc and washed with brine. The organic layer wasdried (Na₂SO₄), filtered and concentrated. The crude was chromatographed(silica, methanol/dichloromethane) to give the desired compound (0.32 g,50% yield) as a yellow oil. ¹HNMR (CDCl₃, ppm): 7.53 (brs, 1H), 6.24(brs, 1H), 4.47 (brs, 2H), 3.65-3.51 (brd, 2H), 1.48-1.28 (brd, 9H),0.96 (brs, 4H).

Step 16b.

The title compound was prepared using procedures similar to thosedescribed above; ESI-MS m/z=424.30 [M+H]⁺. The following examples wereprepared using procedures similar to those described above:

ESIMS (M − H)⁻ Exam- or ple Structure (M + H)⁺ 5

463.13 [M − H]⁻ 6

452.10, 454.10 [M − H]⁻ 7

431.16 [M + H]⁺ 8

413.17 [M + H]⁺ 9

429.14, 431.14 [M + H]⁺ 10

456.14 [M + H]⁺ 11

438.33 [M + H]⁺ 12

454.30, 456.30 [M + H]⁺ 17

446.21 [M + H]⁺ 18

462.18, 464.18 [M + H]⁺ 19

450.25 [M + H]⁺ 26

464.30 [M + H]⁺ 36

422.10 [M + H]⁺ 37

420.20 [M + H]⁺ 38

436.20 [M + H]⁺ 39

462.20 [M + H]⁺ 40

498.20 [M + H]⁺ 41

410.15 [M + H]⁺ 42

418.15 [M + H]⁺ 43

444.15 [M + H]⁺ 44

436.30 [M + H]⁺ 45

499.25 [M + H]⁺ 46

490.30 [M + H]⁺ 47

409.15 [M + H]⁺ 48

460.30 [M + H]⁺ 49

460.30 [M + H]⁺ 50

446.25 [M + H]⁺ 51

470.25 [M + H]⁺ 52

498.25 [M + H]⁺ 53

476.25 [M + H]⁺ 54

476.25 [M + H]⁺ 55

448.20 [M + H]⁺ 56

490.30 [M + H]⁺ 57

476.25 [M + H]⁺ 58

462.15 [M + H]⁺ 59

462.15 [M + H]⁺ 60

450.30 [M + H]⁺ 61

448.25 [M + H]⁺ 62

458.15 [M + H]⁺ 63

458.00 [M + H]⁺ 64

512.25 [M + H]⁺ 65

492.35 [M + H]⁺ 66

436.25 [M + H]⁺ 67

464.30 [M + H]⁺ 68

478.35 [M + H]⁺ 69

506.35 [M + H]⁺ 70

540.30 [M + H]⁺ 71

492.20 [M + H]⁺ 72

493.20 [M + H]⁺ 73

456.05 [M + H]⁺ 74

482.10 [M + H]⁺ 75

483.20 [M + H]⁺ 76

[M + H]⁺

The following examples are prepared using procedures similar to thosedescribed above:

Exam- ple Structure 20

21

22

23

24

25

27

28

29

30

31

32

33

34

35

Biological Activity

Methods: HepAD38 cells were maintained as previously reported (Ladner etal, Antimicrob. Agents Chemother. 1997, 4, 1715). Briefly, cells werepassaged upon attaining confluency in DMEM/F12 media in the presence of10% FBS, Penn/Strep, 250 μg/mL G418, and 1 ug/ml tetracycline. Compoundswere screened by first washing cells three times with PBS to removetetracycline, and plating in 96 well plates at 35,000 cells/well.Compounds dissolved in DMSO were then diluted 1:200 into wellscontaining cells. Five days after compound addition, material washarvested for analysis. For an extended 8 day analysis, cells wereplated and treated as described above, but media and compound wererefreshed on day 2 and day 5 post initial treatment.

On harvest day, virion DNA was obtained by lysing with Sidestep Lysisand Stabilization Buffer and then quantified via quantitative real timePCR. Commercially available ELISA kits were used to quantitate the viralproteins HBsAg (Alpco) or HbeAg (US Biological) by following themanufacturer's recommended protocol after diluting samples to match thelinear range of their respective assays. Irrespective of readout,compound concentrations that reduce viral product accumulation in thecell lysates or supernatants by 50% relative to no drug controls (EC₅₀)are reported; EC₅₀ ranges are as follows: A<0.1 μM; B 0.1-0.2 μM; C>0.2μM.

Compound toxicity was evaluated by seeding cells at 15,000 cells/welland treating with compound as described above. Three days after compoundaddition, cells were treated with ATPLite reagent and compoundconcentrations that reduce total ATP levels in wells by 50% relative tono drug controls (CC₅₀) are reported; CC50 ranges are as follows: A>25μM; B 10-25 μM; C<10 μM.

TABLE 1 Summary of Activities Compd. HepAD38 Compd. HepAD38 Number EC₅₀(μM) Number EC₅₀ (μM) 1 C 2 C 3 C 4 A 5 B 6 A 7 B 8 A 9 C 10 A 11 A 12 A13 A 14 A 15 A 16 C 17 A 18 A 19 A 26 A 36 C 37 A 38 B 39 A 40 A 41 C 42B 43 C 44 A 45 A 46 C 47 C 48 A 49 B 50 A 51 A 52 C 53 A 54 A 55 A 56 B57 A 58 B 59 A 60 A 61 B 62 C 63 C 64 B 65 A 66 B 67 A 68 B 69 C 70 A 71A 72 A 73 A 74 C 75 B 76 C

TABLE 2 Summary of Cytotoxicity Compd. ATPlite Compd. ATPlite NumberCC₅₀ (μM) Number CC₅₀ (μM) 10 A 11 A 12 A 15 A 17 A 18 A 19 A 26 A 51 A53 A 60 A 72 A 73 A

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound represented by Formula (I), or a pharmaceuticallyacceptable salt thereof:

wherein: W and Y are N and Z is CR¹⁰; or W is C, one of Y and Z is N andthe other is NR¹¹; or W, Y and Z are each N; R¹⁰ is hydrogen, halo, oroptionally substituted C₁-C₆ alkyl; R¹ is hydrogen, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₃-C₈ cycloalkyl; orR¹ and R³ are independently hydrogen or optionally substituted C₁-C₆alkyl; R² is selected from the group consisting of optionallysubstituted C₃-C₆ cycloalkyl, optionally substituted 3- to 8-memberedheterocyclic, optionally substituted aryl, and optionally substitutedheteroaryl; R⁴ is selected from the group consisting of hydrogen, halo,hydroxy, protected hydroxy, amino, optionally substituted amino,optionally substituted C₁-C₆ alkyl, and optionally substituted C₁-C₆alkoxy; Alternatively, R¹ and R² are taken together with the carbon atomto which they are attached to form optionally substituted C₃-C₈cycloalkyl, optionally substituted C₃-C₈ cycloalkenyl, or optionallysubstituted 3- to 8-membered heterocyclic; Alternatively, R¹ and R³ aretaken together with the carbon atoms to which they are attached to forman olefinic double bond; Alternatively, R² and R⁴ are taken togetherwith the carbon atoms to which they are attached to form optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₃-C₈ cycloalkenyl,or optionally substituted 3- to 8-membered heterocyclic; Alternatively,R³ and R⁴ are taken together with the carbon atom to which they areattached to form optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted C₃-C₈ cycloalkenyl, or optionally substituted 3- to8-membered heterocyclic; Alternatively, R¹, R², R³ and R⁴ are takentogether with the carbon atoms to which they are attached to formoptionally substituted aryl or optionally substituted heteroaryl; R⁵ isselected from the group consisting of optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₈ alkenyl, optionally substitutedC₂-C₈ alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted 3- to 8-membered heterocyclic, optionally substituted aryl,optionally substituted heteroaryl, and -L-R¹²; wherein L is selectedfrom a group consisting of —O—, —S—, —NR¹¹—, —C(O)—, —C(O)O—, —OC(O)—,—C(O)N(R¹¹)—, —N(R¹¹)C(O)—, —OC(O)N(R¹¹)—, —N(R¹¹)C(O)O—,—N(R¹¹)C(O)N(R¹¹)—, —S(O)—, —S(O)₂—, —S(O)₂N(R¹¹)—, —N(R¹¹)S(O)₂—,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted 3- to 8-membered heterocyclic,optionally substituted aryl, and optionally substituted heteroaryl; R¹²is selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted 3- to 8-membered heterocyclic, optionallysubstituted aryl, and optionally substituted heteroaryl; R⁶ is hydrogenor optionally substituted C₁-C₆ alkyl; and R⁷ is an optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₃-C₈ cycloalkyl. 2.The compound of claim 1, wherein R⁵ is selected from one of thefollowing by removal of one hydrogen atom:

each of the above shown groups is optionally substituted and isconnected to the pyrazole or triazole ring through a carbon atom or, ifpossible, a nitrogen atom.
 3. The compound of claim 1, wherein R⁵ is-L-R¹², wherein -L- is —O—, —N(R¹)C(O)—, —OC(O)N(R¹)—, —N(R¹¹)C(O)O—,—N(R¹¹)C(O)N(R¹¹)—, —N(R¹¹)S(O)₂—, or one of the following by removal oftwo hydrogen atoms:

wherein each of the above shown groups is optionally substituted; andR¹² is selected from one of the following by removal of one hydrogenatom:

wherein each of the above shown groups is optionally substituted.
 4. Thecompound of claim 1, wherein R⁷ is selected from the group consistingof:


5. The compound of claim 1, represented by Formula (IIa), or apharmaceutically acceptable salt thereof,

wherein E¹, E², E³, E⁴, E⁵, and E⁶ are each independently selected fromthe group consisting of absent, —CR¹³R¹⁴—, —NR¹¹—, —O—, —C(O)—, —S(O)—,—S(O)₂—, and —S—, provided that at least one of E¹, E², E³, E⁴, E⁵, andE⁶ is not absent; R¹³ and R¹⁴ at each occurrence are independentlyhydrogen, halo, or optionally substituted C₁-C₆ alkyl; and R¹, R³, R⁵,R⁶, and R⁷ are as defined claim
 1. 6. The compound of claim 1,represented by Formula (IIIa) or Formula (IVa), or a pharmaceuticallyacceptable salt thereof,

wherein E¹, E², E³, E⁴, E⁵, and E⁶ are each independently selected fromthe group consisting of absent, —CR¹³R¹⁴—, —NR¹¹—, —O—, —C(O)—, —S(O)—,—S(O)₂—, and —S—, provided that at least one of E¹, E², E³, E⁴, E⁵, andE⁶ is not absent; R¹³ and R¹⁴ at each occurrence are independentlyhydrogen, halo, or optionally substituted C₁-C₆ alkyl; and R¹, R³, R¹¹,R⁵, R⁶, and R⁷ are as defined claim
 1. 7. The compound of claim 1,represented by Formula (Va), or a pharmaceutically acceptable saltthereof,

wherein E¹, E², E³, E⁴, E⁵, and E⁶ are each independently selected fromthe group consisting of absent, —CR¹³R¹⁴—, —NR¹¹—, —O—, —C(O)—, —S(O)—,—S(O)₂—, and —S—, provided that at least one of E¹, E², E³, E⁴, E⁵, andE⁶ is not absent; R¹³ and R¹⁴ at each occurrence are independentlyhydrogen, halo, or optionally substituted C₁-C₆ alkyl; and R¹, R³, R⁵,R⁶, and R⁷ are as defined claim
 1. 8. The compound of claim 1,represented by Formula (VI), or a pharmaceutically acceptable saltthereof,

wherein at least one of E¹, E², E³, E⁵, and E⁶ is present, and E¹, E²,E³, E⁵, and E⁶ are each independently selected from the group consistingof absent, —CR¹³R¹⁴—, NR¹¹—, —O—, —C(O)—, —S(O)—, —S(O)₂—, and —S—,provided that at least one of E¹, E², E³, E⁴, E⁵, and E⁶ is not absent;R¹³ and R¹⁴ at each occurrence are independently hydrogen, halo, oroptionally substituted C₁-C₆ alkyl; W, Y, Z, R³, R⁴, R⁵, R⁶, and R⁷ areas defined claim
 1. 9. The compound of claim 1, represented by Formula(VIIa), Formula (VIIb), Formula (VIIc), or Formula (VIId), or apharmaceutically acceptable salt thereof,

wherein W, Y, Z, R¹, R³, R⁴, R⁵, and R⁷ are as defined claim
 1. 10. Thecompound of claim 1, selected from the compounds set forth below or apharmaceutically acceptable salt thereof: Com- pound Structure 1

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11. A pharmaceutical composition, comprising a compound according toclaim 1 and a pharmaceutically acceptable carrier or excipient.
 12. Amethod of treating or preventing an HBV infection in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound or a combination of compounds accordingto claim
 1. 13. The method of claim 12, further comprising administeringto the subject at least one additional therapeutic agent selected fromthe group consisting of HBV polymerase inhibitors, interferon, viralentry inhibitors, viral maturation inhibitors, capsid assembly or coreprotein inhibitors or modulators, reverse transcriptase inhibitors,TLR-agonists, inducers of cellular viral RNA sensor, therapeuticvaccines, RNA interence (RNAi) or small interfering RNA (siRNA) andcombinations thereof.
 14. The method of claim 13, wherein the compoundand the at least one additional therapeutic agent are co-formulated. 15.The method of claim 13, wherein the compound and the at least oneadditional therapeutic agent are co-administered.
 16. The method ofclaim 13, wherein administering the compound allows for administering ofthe at least one additional therapeutic agent at a lower dose orfrequency as compared to the administering of the at least oneadditional therapeutic agent alone that is required to achieve similarresults in prophylactically treating an HBV infection in an individualin need thereof.
 17. The method of claim 13, wherein the subject isrefractory to at least one compound selected from the group consistingof a HBV polymerase inhibitor, interferon, viral entry inhibitor, viralmaturation inhibitor, distinct capsid assembly modulator, inducer ofcellular viral RNA sensor, therapeutic vaccine, antiviral compounds ofdistinct or unknown mechanism, and combination thereof.
 18. The methodof claim 13, wherein the administering of the compound reduces viralload in the subject to a greater extent compared to the administering ofat least one compound selected from the group consisting of a HBVpolymerase inhibitor, interferon, viral entry inhibitor, viralmaturation inhibitor, distinct capsid assembly modulator, inducer ofcellular viral RNA sensor, therapeutic vaccine, antiviral compounds ofdistinct or unknown mechanism, and combination thereof.
 19. The methodof claim 13, wherein the method results in a lower incidence of viralmutation and/or viral resistance than administering a compound selectedfrom the group consisting of a HBV polymerase inhibitor, interferon,viral entry inhibitor, viral maturation inhibitor, distinct capsidassembly modulator, inducer of cellular viral RNA sensor, therapeuticvaccine, antiviral compounds of distinct or unknown mechanism, andcombination thereof.